Further Reading (vol 2): Research Breakthroughs that led to mRNA COVID-19 Vaccines

It’s been quite exhilarating for Conny and I to see our article about the vaccine supply chain go viral (no pun intended). The most exciting part of it all are the emails from readers who share insights or ask questions. And as a result we continue to read and find more interesting articles.

My previous list of links for further reading was, inadvertently, focused on activities that happened during 2020 and what happened behind the scenes at Pfizer, BioNTech, and Moderna. This week’s set of links looks further back into history and introduces people and events related to mRNA research going as far back as the 1970s.

As always, please send feedback and suggestions for more articles worth reading to jn@jonasneubert.com.

How COVID unlocked the power of RNA vaccines

in Nature, by Elie Dolgin, published 12 January 2021

The article starts like so many mRNA vaccine stories: New strain discovered, a few days later the sequence gets published, a few additional days later the RNA is designed and synthesized, studies in cells and mice follow shortly. Except, this one is about the H1N1 virus, the company is Novartis, and the year is 2013. Manufacturing mRNA at scale was not feasible in 2013 and Novartis sold its vaccine business in 2015. The information-packed article also covers the funding history of mRNA vaccine research, several mRNA vaccine projects for other diseases, strategies for getting rid of the cold storage requirement, side effects, self-amplifying mRNA vaccines, and a lot more.

A gamble pays off in ‘spectacular success’: How the leading coronavirus vaccines made it to the finish line

in Washington Post, by Carolyn Y. Johnson, published 6 December 2020

Read this article for an introduction to another group of scientists who worked on mRNA vaccines in 2013. Among the many people introduced in this article are NIH scientist Barney Graham and University of Texas professor Jason McLellan whose labs modified the genetic sequence for the now famous Coronavirus spike protein. This genetic change is what makes the protein stable in its prefusion conformation, meaning that it looks the same when arriving by itself as it would when attached to the virus, a prerequisite for the vaccine. This work happened in 2013 (with a different Coronavirus, of course) but the paper reporting on the success got rejected for publication five times due to “lack of significance” before it appeared in PNAS in 2017. Today, Graham is at the center of the NIH-Moderna collaboration for Moderna’s COVID-19 vaccine.

They spent 12 years solving a puzzle. It yielded the first COVID-19 vaccines.

in National Geographic, by Jillian Kramer, published December 31, 2020

The duo Graham & McLellan from the article above are the main characters of this piece. This one fills in the details of all the work, collaboration, and fair amount of luck that led to the discovery (and, yes, patenting) of the 2P mutation that stabilized the spike protein. Start reading for the story about a postdoc returning from international travel with a respiratory infection, stay for the explanation of X-ray crystallography versus cryogenic electron microscopy. By the way, not only Pfizer-BioNTech and Moderna use this mutation in their vaccine, Novavax and Johnson & Johnson also do.

‘Redemption’: How a scientist’s unwavering belief in mRNA gave the world a Covid-19 vaccine

in The Telegraph, by Saray Newey and Paul Nuki, published 2 December 2020

After reading many other portraits of researchers whose work led to the mRNA COVID-19 vaccines, those about Katalin Karikó stand out for just how much the cards seemed to be stacked against her. After a decade of doing mRNA research in Hungary her position got defunded. Another decade and a move to the US later, she fell off the tenure track at UPenn due to lack of funding for her mRNA research. Another decade later she was still working on mRNA and discovered, with collaborator Drew Weissmann, the nucleoside substitution that prevents the human body from “over-reacting” to synthetic mRNA. Both the Pfizer-BioNTech and Moderna COVID-19 vaccines use this technique. On January 20th I had an opportunity to be star-struck: Out of nowhere, Professor Karikó responded to a tweet of mine to clarify some terminology!

A vaccine 50 years in the making: How a London scientist laid the foundations for the coronavirus jab decades ago

in Independent, by Shaun Lintern, published 23 January 2021

Among the 400 scientific papers Gregory Gregoriadis wrote during his career is one he co-authored in 1971 that first proposed the use of liposomes as delivery mechanism for drugs and one published in Nature in 1974 about liposomes as adjuvant (immune system agitator) for vaccines. Oh, and he also wrote the book on “Liposome Technology”. A few days ago Gregoriadis received his first dose of the Pfizer vaccine which contains liquid nanoparticles described by the article as “direct descendent” of his research. To be honest, the article is a bit light on details, but check it out for the no-nonsense quote about how a scientific discovery came about at the end.

Advances in mRNA Vaccines for Infectious Diseases

in Frontiers in Immunology, Cuiling Zhang et al, published 27 March 2019

Admittedly, I did not read this one all the way. This is an academic review paper of the state of mRNA vaccine research as of March 2019.